Research
Background
Small organic compounds that bind to proteins and modulate their function are called bioactive small molecules. They serve as drugs, starting points for drug development, and probes for chemical biology. The identification of bioactive small molecules is one of the most critical steps in a drug discovery program. It is a principal task of medicinal chemists. High throughput screening (HTS), i.e. the screening of large compound libraries at disease-relevant protein targets has proven its value to discover bioactive molecules. These may serve as starting points in drug development programs or as probes in chemical biology. New innovative and broadly applicable concepts to screen libraries of small molecules at disease-relevant proteins are badly needed. The concept to synthesize and pool large combinatorial DNA-encoded small molecule library and to screen the whole encoded library as a pool at immobilized protein targets in a single selection experiment is an innovative approach to bring HTS into academia.
Sequencing of the human genome provided the protein-coding sequences of all genes, including that subset of proteins capable of binding low molecular weight compounds, the so-called “druggable genome”. Typical members of the “druggable genome”, i.e. traditional drug targets, are for example G protein-coupled receptors and enzymes such as kinases. However, the number of proteins associated with diseases is much larger than the druggable genome. Many disease-related proteins, for instance those that take part in protein-protein interactions, are promising, yet difficult targets in drug research. Screening of large DNA-encoded libraries holds promise to identify small molecule ligands for these difficult protein targets.
What are our methods?
Encoding of small molecules allows for pooling of small molecule libraries. Putative bioactive small molecules can be identified through an efficient selection assay:
- Incubation of a large pooled encoded small molecule library with an immobilized target protein
- Washing steps to remove the non-binding small molecules
- PCR-amplification of the selected small molecules and Illumina sequencing to identify the protein binders
- Follow-up assays for validation of protein binders and elucidation of mode of action
We are applying a broad range of methods from two very different worlds: chemistry and molecular biology.
We
- synthesize functionalized small molecule scaffolds by organic preparative chemistry
- couple these scaffolds to DNA
- perform combinatorial chemistry on the DNA-coupled scaffolds
- develop novel DNA-compatible chemical methods to furnish the library
- use methods from molecular biology to encode each chemical step
- develop novel selection assay approaches
in order to
- obtain a large, pooled small molecule library with hundreds of thousands of members
- screen the pooled library at promising drug targets, also from collaboration partners,
to identify novel bioactive small molecules.